All cells rely on the regulated movement of inorganic ions across cell membranes to perform essential physiological functions. Electrical excitability, synaptic plasticity, and signal transduction are examples of processes in which changes in ion concentration play a critical role. In general, the ion channels that permit these changes are proteinaceous pores consisting of one or multiple subunits, each containing two or more membrane-spanning domains. Most ion channels have selectivity for specific ions, primarily Na+, K+, Ca2+, or Cl−, by virtue of physical preferences for size and charge. Electrochemical forces, rather than active transport, drive ions across membranes, thus a single channel may allow the passage of millions of ions per second. Channel opening, or “gating” is tightly controlled by changes in voltage or by ligand binding, depending on the subclass of channel. Ion channels are attractive therapeutic targets due to their involvement in so many physiological processes, yet the generation of drugs with specificity for particular channels in particular tissue types remains a major challenge.
Voltage-gated ion channels open in response to changes in membrane potential. For example, depolarization of excitable cells such as neurons result in a transient influx of Na+ ions, which propagates nerve impulses. This change in Na+ concentration is sensed by voltage-gated K+ channels which then allow an efflux of K+ ions. The efflux of K+ ions repolarizes the membrane. Other cell types rely on voltage-gated Ca2+ channels to generate action potentials. Voltage-gated ion channels also perform important functions in non-excitable cells, such as the regulation of secretory, homeostatic, and mitogenic processes. Ligand-gated ion channels can be opened by extracellular stimuli such as neurotransmitters (e.g., glutamate, serotonin, acetylcholine), or intracellular stimuli (e.g., cAMP, Ca2+, and phosphorylation).
Calcium channels include voltage-gated and non-voltage-gated classes. Voltage-gated calcium channels can be further subdivided into T, L, N, P, and Q subtypes. T-type channels transiently activate at negative potentials while the other subtypes activate at positive potentials. The al subunits of voltage-gated Ca2+ channels are similar to the a subunits of voltage-gated sodium channels, and contain four repeat regions, each containing six transmembrane domains. The P/Q type a subunits are expressed in the brain, motor neurons, and kidney and are important for transmitter release. N-type α1 subunits are expressed in the central and peripheral nervous systems and are also important for transmitter release. L-type α1 subunits are expressed in heart, lung, smooth muscle, fibroblasts, brain, pancreas, and the neuroendocrine system and mediate coupling of muscular excitation and contraction. R-type subunits are expressed in brain and muscle and are important for transmitter release. T-type subunits are expressed in brain, cardiac, and smooth muscle. Other α1 subunits are expressed in retina and skeletal muscle. Alpha-1 subunits associate with auxiliary subunits that regulate the function of the channels for example, by modifying the kinetics of Ca2+ influx, Ca2+ current amplitude, or voltage-dependence.
Non-voltage-gated Ca2+ channels include ligand-gated channels. These channels are Ca2+ ATPases which are expressed in muscle and other tissues. Mutations in Ca2+ ATPases causes Brody myopathy (ATP2A1), Darier-White disease and Keratosis follicularis (ATP2A2), deafness and vestibular imbalance (ATP2B2). Another important class of non-voltage-gated Ca2+ channel is the intracellular class, which include ryanodine receptors, inositol -1,4,5-triphosphate (IP3) receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) receptor, and sphingolipid receptor (EDG1). In general, intracellular Ca2+ channels form homotetrameric complexes. They are stimulated by second messengers such as elevation in intracellular Ca2+ levels, ryanodine, caffeine, IP3, NAADP, and sphingosine-1-phosphate. The release of intracellular Ca2+ through these channels leads to amplification of signaling events.
Genetic or pharmacological perturbations in ion channel function can have dramatic clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and episodic ataxia are a few examples of heritable diseases resulting from mutations in ion channel subunits. Toxic side affects such as arrhythmia and seizure which are triggered by certain drugs are due to interference with ion channel function (Sirois and Atchison, Neurotoxicology, 17(1):63-84, 1996; Keating,M. T., Science 272:681-685, 1996). Drugs are useful for the therapeutic modulation of ion channel activity, and have applications in treatment of many pathological conditions, including hyptertension, angina pectoris, myocardial ischemia, asthma, bladder overactivity, alopecia, pain, heart failure, dysmenorrhea, type II diabetes, arrhythmia, graft rejection, seizure, convulsions, epilepsy, stroke, gastric hypermotility, psychoses, cancer, muscular dystrophy, and narcolepsy (Coghlan, M. J., et al., J. Med. Chem. 44:1627-1653, 2001; Ackerman. M. J., and Clapham, D. E., N. Eng. J. Med. 336:1575-1586, 1997). The growing number of identified ion channels and further understanding of their complexity will assist in future efforts at therapies that modify ion channel function.